Fragility of the human skeleton is characterized by low bone mass, microarchitectural deterioration and changes in the mineralized extracellular matrix, including accumulation of unrepaired microdamage. These reductions in bone quantity and quality are directly responsible for over 2 million atraumatic fractures in the U.S. annually. Most osteoporotic patients do not regain their pre-fracture function and many suffer chronic, disabling pain and require nursing home placement. While therapeutic interventions have primarily focused on improvement in bone mass, it is now recognized that changes in local bone microarchitecture and material properties (i.e. bone quality) may contribute significantly to fracture risk. The importance of bone quality is strongly implicated by the dramatic increase in fractures associated with aging, even for similar levels of bone mass. Moreover, some drug treatments at least transiently reduce fracture risk without appreciably changing bone mass. Despite this evidence, the role of bone quality in the progression and treatment of skeletal fragility is poorly understood. Furthermore, although age-related changes in bone matrix are known, it is unclear how the local failure properties of bone change with age. The goal of this research project is to investigate age-related changes in bone quality by evaluating trabecular level stresses and matrix property changes associated with the initiation and progression of microdamage. The Specific Aims are to: 1) Evaluate microdamage initiation in human trabecular bone subjected to uniaxial compressive loading as a function of age, gender, and anatomical site, 2) Evaluate microdamage progression in human trabecular bone subjected to cyclic loading as a function of age, gender, and anatomical site, 3) Evaluate microdamage initiation in human trabecular bone subjected to combined axial and torsional loading as a function of age and gender, and 4) Determine the effects of turnover rate and time of remodeling suppression on microdamage initiation and progression. An approach combining mechanical testing, finite element analysis, microdamage labeling, and FTIR analysis of mineral and matrix parameters will be used to better understand how and why microdamage initiates and progresses in trabecular bone under varying loading conditions and whether the associated microstructural stresses and strains change with aging or are different between men and women or between femoral, calcaneal and vertebral trabecular bone.